FROM IN VITRO HIGH CONTENT SCREENINGS TO MAMMALIAN IN VIVO ASSAYS: THE CASE OF miR‐34/449?s ROLE DURING CEREBROCORTICAL DEVELOPMENT

GONZALEZ, PAULA; AGUIRRE, PAULA A.; ESK, CHRISTOPHER; MIERZWA, BEATA; SOMMER, CHRISTOPH; GERLICH, DANIEL WOLFRAM ; FEDEDA, JUAN PABLO

Buenos Aires

Congreso; LIII REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN BIOQUÍMICA Y BIOLOGÍA MOLECULAR (SAIB); 2017

SOCIEDAD ARGENTINA DE INVESTIGACIÓN BIOQUÍMICA Y BIOLOGÍA MOLECULAR

Abstract: During mammalian cerebral cortex development, spindle orientation defects result in severe neurodevelopmental disorders. Proper orientation of the mitotic spindle determines the plane of cellular cleavage in neural progenitors. However, the precise mechanisms that control this important event are not fully understood. Using a combination of high‐content screening and mouse genetics, we identified miR‐34/449 family as key regulator of mitotic spindle orientation in the developing cerebral cortex. By screening through all cortically expressed microRNAs in vitro, we show that several members of the miR‐34/449 family control mitotic duration and spindle rotation. Analyzing miR‐34/449 knockout (KO) mouse embryos, we found significant spindle misorientation phenotypes in cortical progenitors, resulting in an excess of radial glia cells at the expense of intermediate progenitors and a significant delay in neurogenesis. Additionally, we identify the junction adhesion molecule‐A (JAM‐A) as a key target for miR‐34/449 in the developing cortex that might be responsible for those defects. Our data indicate that miR-34/449-dependent regulation of mitotic spindle orientation is crucial for cell fate specification during mammalian neurogenesis in the developing cortex. Finally, using a similar high-content screening pipeline, we also identified novel cortical microRNA candidates regulating cell migration, which are being validated in vivo.